Current progress in human genome analysis has lead to the identification of genes associated with a variety of disorders. The analyses of these disorder-associated genes are revealing complicated relationships between the actions of causative gene(s) (or the aberrant action of normal genes associated with disorders) and the action of gene(s) that suppress disorders. That is, almost all the disorders occurring in humans are thought to be caused by a collapse in the balance between the action of disease-causing aberrant genes (or aberrant action of normal genes associated with disorders) and the action of normal suppressor genes that compete with aberrant genes. Such a view-point may be applicable to almost all the disorders ranging from stomach ulcer to neurodegenerative diseases, indicating, in other words, a possible presence of normal genes that suppress a majority of disorders (or disorder suppressor genes) in the genome. Needless to say, development of an efficient method of screening for such genes undoubtedly would enable the discovery and identification of useful genes expressing specific therapeutic effects on a variety of human disorders, including intractable diseases for which no treatment has yet been found.
Conventionally, a suppressor gene for a particular disorder was screened mostly by using a method that searched for a molecule that suppressed a biochemical function of a causative gene using the biochemical function as an index. However, such a method cannot be applied to cases where the biochemical function of the causative gene has not been elucidated. Furthermore, even if the biochemical function has been identified, the search for drugs based on the function may not directly lead to a molecule capable of curing the disorder when the biochemical function is not the direct cause of the onset of the disorder. In fact, even if a gene has been proved to be a causative of a particular disorder from epidemiological, genetic, or other studies, the biochemical function of the gene cannot be often identified, and, moreover, even if it is identified, it is difficult to clarify whether the identified function is the direct cause for the onset of the disorder. For example, although it has been demonstrated that a mutation in the α-synuclein gene, which has been identified as one of the Parkinson's disease (PD)-associated genes (Polymeropoulos, M. H. et al., 1997, Science 276: 2045-2047), is definitely the gene that causes the onset of PD, the biochemical function of α-synuclein has not so yet been elucidated. An Alternative example is the ATM gene, causative of ataxia telangiectasia (spinocerebellar degeneration with capillarectasia), in which although the only known biochemical function of ATM is a PI3 kinase-like activity, it is entirely unclear whether the aberration of this biochemical function causes the onset of the disorder. Thus, it is extremely difficult to develop a therapeutic molecule for a disease based on the mere identification of a causative gene.
Systems that attempt screening through a more functional method have been developed. One of them is a method of screening for genes and molecules that suppress cell death induced by disease-causing genes, which has been conventionally referred to as the death-trap method (D'Adamio, L. et al., Semin. Immunol. 1997, 9: 17-23). However, due to the extremely low efficiency in screening when using only the conventional death-trap method, this method has not so far become an effective screening method.
As described above, almost all the disorders occurring in humans are thought to be caused by a collapse in the balance between the action of disease-causing aberrant genes (or aberrant action of normal genes associated with disorders) and the action of normal suppressor genes that compete with aberrant genes. Therefore, it is highly likely that suppressor genes for a majority of disorders are present in the genome. Thus, screening of a cDNA library covering the human genome using the death-trap method may theoretically lead to the discovery of disorder suppressor genes. However, it is extremely difficult to discover such a suppressor gene out of the vast genome even by conducting this screening method, and in fact, no disorder suppressor gene has so far been found using the death-trap method even several years after its establishment. Therefore, a method capable of more efficiently screening disorder suppressor genes has been anticipated.